Functionalization of non-activated C-H bonds in ketones and imines with HF/SbF5/CCl4

Article abstract of DOI:10.1016/S0040-4020(02)00692-0

Reaction of cyclic ketones 2-6 and imines 15-17 in HF/SbF₅ in presence of CCl₄ yield hydroxy or fluoroderivatives, hydride abstraction occurring at a site located far from the functional group. Whereas ketones 2-5 yield only hydroxy derivatives, through cyclic carboxonium ion, imines 15, 16 N-protonated in the media conditions give only fluoroderivatives 18, 19, respectively, after quenching with HF-pyridine. Ring contraction is operative when starting from large membered ring ketones 24 and 25, and imine 26, leading to a mixture of hydroxy or fluoro cyclohexanones and/or cycloheptanones.

Full text of DOI:10.1016/S0040-4020(02)00692-0

Tetrahedron 58 (2002) 6643–6649
Functionalization of non-activated C–H bonds in ketones and
imines with HF/SbF5/CCl4
*
Sebastien Thibaudeau, Agnes Martin-Mingot, Marie-Paule Jouannetaud and J. C. Jacquesy
´
`
` ´ ´
Laboratoire ‘Synthese et Reactivite des Substances Naturelles’, UMR 6514, 40, Avenue du Recteur Pineau, F-86022 Poitiers Cedex, France
Received 29 April 2002; revised 3 June 2002; accepted 24 June 2002
Abstract—Reaction of cyclic ketones 2–6 and imines 15–17 in HF/SbF5 in presence of CCl4 yield hydroxy or fluoroderivatives, hydride
abstraction occurring at a site located far from the functional group. Whereas ketones 2–5 yield only hydroxy derivatives, through cyclic
carboxonium ion, imines 15, 16 N-protonated in the media conditions give only fluoroderivatives 18, 19, respectively, after quenching with
HF–pyridine. Ring contraction is operative when starting from large membered ring ketones 24 and 25, and imine 26, leading to a mixture of
hydroxy or fluoro cyclohexanones and/or cycloheptanones. q 2002 Published by Elsevier Science Ltd.
1. Introduction
2. Results and discussion
Functionalization of non-activated C–H bonds remains a
major challenge in organic chemistry. As shown by Olah
and co-workers, functionalization of s-bonds can be
carried out with superacids (or their salts) by protolysis or
by reaction with electrophiles: halogens, protonated
ozone, hydrogen peroxide, chloromethyl ions, or nitro-
nium and nitrosonium ions.1–9 These results have been
accounted for by Olah who developed the concept of s
basicity of C–C or C–H bond sharing its electron pair
with an electrophile, through a two-electron-three
centre bonded intermediate or transition state.10
Functionalized substrates being protonated in superacids,
reaction with an electrophile will occur at a rich
electron site far from the protonated functional group.11
We wish to report here the hydroxylation or fluorination
of various ketones and imines in HF–SbF5 in presence of
CCl4.
2.1. Reaction of acyclic ketones and imines in
HF/SbF5/CCl4
The results reported in Tables 1 and 2 show that most
substrates yield hydroxy and/or fluoro derivatives, which
after flash-chromatography over silica gel, have been
identified by NMR spectroscopy. Firstly it should be
pointed out that no reaction was observed in HF/SbF5 in
the same experimental conditions (except with imines
leading to the corresponding ketones) after hydrolysis.
The observed reactivity of the substrates in HF/SbF5/CCl4
can be accounted for by hydride abstraction by the
electrophilic trichloromethyl cation CClþ3 .12,13 The sur-
prising hydride abstractive power of this ion has been
assumed by Olah to be due to protosolvatation or
complexation by the Lewis acid SbF5, leading to a
‘superelectrophile’ (Fig. 1).14
Table 1. Reaction of ketones with HF/SbF5/CCl4
Entry
Substrate
Temperature (8C)
Time (min)
Quenching conditions
Products (%)
No reaction
1
2
3
4
5
6
7
8
9
1
2
2
3
4
5
6
6
7
230
230
0
230
230
230
230
230
230
30
5
30
10
5
5
3
3
30
A or B
A or B
A or B
A or B
A or B
A or B
A
8þ9 (67) (1/3 ratio)
10 (44)
10 (82)
11 (80)
11 (92)
13 (50)þ12 (12)
13 (32)þ12 (20)
No reaction
B
A
Keywords: ketones; imines; iminium.
*
Corresponding author. Tel.: þ33-5-49-453-859; fax: þ33-5-49-453-501; e-mail: marie.paule.jouannetaud@univ-poitiers.fr
0040–4020/02/$ - see front matter q 2002 Published by Elsevier Science Ltd.
PII: S0040-4020(02)00692-0

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S. Thibaudeau et al. / Tetrahedron 58 (2002) 6643–6649
Table 2. Reaction of imines in HF/SbF5/CCl4
Entry
Substrate
Temperature (8C)
Time (min)
Quenching conditions
Products (%)
1 (qqtive)
1
2
3
4
5
6
7
14
15
15
16
16
17
17
230
0
0
230
230
230
230
30
30
30
30
30
30
30
A or B
A
B
A
B
A
B
10 (21)þ18 (46)þ2 (9)
18 (68)
11 (14)þ19 (24)
19 (67)
13 (20)þ12 (20)
13 (19)þ12 (36)
(a) HF/SbF5/substrate molar ratio 20/1/0.05; (b) quenching conditions: A: Na2CO3/ice/H2O; B: (1) excess PPHF (HF/pyridine molar ratio 70/30) at reaction
temperature for 15 min, (2) Na2CO3/ice/H2O.
carboxonium ion, preventing the substrate from fluorination
(Scheme 1).17 Hydrolysis only leads to hydroxy derivatives
8–11 (Fig. 2).
Starting from ketone 6, formation of a seven-membered ring
carboxonium ion is more difficult, favoring equilibrium with
the diprotonated species which can be trapped by fluoride
ion. Reaction with HF–pyridine (PPHF) slightly improves
Figure 1.
the yield of fluoro derivative 12, besides alcohol 13. It
should be pointed out that fluorination in the reaction
conditions is a reversible process. Fluoro derivative 12,
placed again in the reaction conditions (HF/SbF5/CCl4)
yields compounds 12 and 13, with similar yields than from
6.
Imines and ketones are N and O-protonated, respectively, in
superacids.15,16 As a result, hydride abstraction by the
electrophile occurs at the more reactive C–H bond, far
located from the protonated functional group. With a
straight chain, hydride abstraction at the (v-1) position
yields a secondary ion which may isomerize to a tertiary
one. Except for ketones 1 and 7 which are too deactivated to
react, all other ketones yield hydroxy and/or fluoro
derivatives (Table 1).11 Ketones 2–5 give only hydroxy
derivatives, whatever the quenching conditions are. This
implies intermediacy of a five or six-membered ring
Very different results were obtained when starting from the
corresponding imines (Table 2). If, as expected imine 14 is
too deactivated to react, conducting only to ketone 1 after
hydrolysis of the corresponding iminium ion, imines 15–17
Scheme 1.
Figure 2.

S. Thibaudeau et al. / Tetrahedron 58 (2002) 6643–6649
6645
2.2. Reaction of cyclic ketones 20–25 and imine 26 in
HF/SbF5/CCl4
The results reported in Table 3 show that the reactivity is
very sensitive to the structure of the substrates.
Cyclic ketone 20 is unreactive in the reaction conditions, the
d-methylene group being probably deactivated by the
cumulative effect of the ring arms. On the other hand
hydride abstraction being easier from an isopropyl group,
4-isopropylcyclohexanone 21 leads to compounds 27 and 28
and to the sole fluoro derivative 27 in the presence of PPHF.
This result, conducting to a 5-fluoro (or hydroxy) ketone,
when compared to other reaction of ketone 4 leading only to
the d-hydroxy derivative through a cyclic carboxonium ion,
implies that the intermediate is an opened ion 35, more
favoured than the strained cyclic carboxonium ion 36
(Fig. 3).
Scheme 2.
always yield fluoroketones, besides hydroxy derivatives.
These results can be explained by the intermediary of the
N-protonated imine, less prone to deprotonation than the
corresponding protonated ketone, and therefore preventing
the formation of the cyclic iminium ion (Scheme 2).
Figure 3.
As expected, treatment of the reaction medium with PPHF
yields the sole fluoro derivatives 18 and 19 in good yields.
Starting from the imine 17, quenching with PPHF only
slightly improves the yield of compound 12. This result
might reflect the equilibrium between ions A and B, the
repulsive interaction between the positive charges in ion A
(separated by four methylene groups) being minimal in this
case.
Table 3 shows that if cycloheptanone 22 is unreactive,
ketones 23 give only complex mixtures, and rearranged
hydroxy and fluoroderivatives are obtained when ketones 24
and 25 are reacted (Fig. 4).
2.2.1. Reaction of cycloundecanone 24. Starting from
ketone 24, the structure of the products is very sensitive to
reaction time. It appears that cycloheptanones 29 and 30 are
the primary products, their precursors isomerizing for
longer reaction time into those of cyclohexanones 31 and
32. The first step implies a hydride abstraction at C-6 to give
ion 37, as far as possible from the protonated carbonyl group
(Scheme 3). Successive ring contractions, involving proto-
nated cyclopropane, will finally yield ion 42. To minimize
the repulsive interaction of the positive charges, ion 42
isomerizes to the more stable tertiary ion 43, precursor of
compounds 29 and 30. Ion 43 can undergo a novel ring
It appears that the imino group could be used as a
‘protecting group’ for ketone function, preventing the
formation of a cyclic carboxonium ion. After hydrolysis,
the latter only leads to the hydroxy compounds(s), whereas
iminium ion, acting as a ‘protected ketone’, yields the
corresponding fluorinated derivative after quenching by
PPHF. This selective novel reaction of functionalization in
superacidic media could be extended to cyclic imines and
ketones as reported below.
Table 3. Reaction of cyclic ketones and imines in HF/SbF5/CCl4
Entry
Substrate
Temperature (8C)
Time
Quenching conditions
Products (%)
No reaction
1
2
3
4
5
6
7
8
20
21
21
22
23
24
24
24
25
25
26
26
230
230
230
0
0
230
0
0
0
0
0
45 min
2 min
2 min
15 min
15 min
10 s
15 min
60 min
15 min
15 min
15 min
15 min
A
A
B
A
A
A
A
A
A
B
A
B
27 (60)þ28 (20)
27 (75)
No reaction
Complex mixture
29þ30 (11) (molar ratio 3/2)
29 (6)þ30 (11)þ31 (6)þ32 (17)
31 (9)þ32 (23)
9
33 (17)þ34 (36, 5)
33 (13)þ34 (29)
10
11
12
33 (19,5)þ34 (12)
0
33 (20)þ34 (10)
(a) HF/SbF5/substrate molar ratio 20/1/0.05; (b) quenching conditions: A: Na2CO3/ice/H2O; B: (1) excess PPHF (HF/pyridine molar ratio 70/30) at reaction
temperature for 15 min, (2) Na2CO3/ice/H2O.

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S. Thibaudeau et al. / Tetrahedron 58 (2002) 6643–6649
Figure 4.
Scheme 3.
contraction through ion 44 to ion 45, precursor of
cyclohexanones 31 and 32.
FSO3H–SbF5–SO2ClF at 2788C yields the 1-n-pentyl-
cyclohexyl tertiary cation20 (Fig. 6).
Our results have to be compared with those previously
published on the ring contraction of cycloalkyl cation in
superacids.18–20 Starting from 1-chloroundecane, in SbF5/
SO2ClF at 2848C Sorensen obtained the 1-methylcyclo-
decyl cation 4618 (Fig. 5).
The more pronounced rearrangement observed in our study
when starting from cycloundecanone 24 in HF/SbF5/CCl4
can be accounted for by the repulsive interaction of the
protonated carbonyle and the carbonium ion in the
intermediate(s).
On the other hand, cycloundecanol when dissolved in
2.2.2. Reaction of cyclododecanone 25 and imine 26. A
similar mechanism can be proposed for the formation of
cycloheptanones 33 and 34 from ketone 25 and imine 26.
Formation of the corresponding cyclohexanones is not
observed, reflecting the stability of the ions precursors of
ketones 33 and 34, in which the interaction of the positive
charges should be small.
Figure 5.
Figure 6.
Surprisingly the 34/33 ratio is about 3 when starting from
ketone 25, and about 0.5 with imine 26. Starting from
ketone 25, we cannot completely rule out intermediacy of a
large-membered ring carboxonium ion precursor of the
hydroxy ketone.

S. Thibaudeau et al. / Tetrahedron 58 (2002) 6643–6649
6647
To conclude, hydroxylation or fluorination of non-activated
bonds of various acyclic or cyclic ketones and imines can be
carried out in superacid in presence of carbon tetrachloride.
Hydride abstraction by the activated trichloromethyl ion
occurs at a site far from the protonated carbonyle or
iminium.
then dry on magnesium sulphate) and products were isolated
by column chromatography over SiO2. Fluoroderivatives
were eluted by EtOAc/P. ether: 5/95, and hydroxyderiva-
tives by EtOAc/P. ether: 50/50.
3.4. Reaction of acyclic ketones and imines
Starting from ketones, formation of a five or six-membered
carboxonium ion accounts for the formation of hydroxy
derivatives after hydrolysis. On the other hand, the
corresponding imines, N-protonated in the reaction con-
ditions, yield hydroxy or fluoroderivatives after trapping of
the intermediate acyclic carbenium ion.
3.4.1. 6-Hydroxyheptan-2-one (8) and 5-hydroxyheptan-
2-one (9). Obtained as a mixture (molar ratio 1/3), from
ketone 2 (quenching condition A) yield 67%. Alcohols are
not separable, so they are acetylated. The acetylated
derivatives are separated by semi-preparative HPLC:
column SI 100, eluent EtOAc/n-hexane: 10/90, flow:
10 mL/min, refractive detector.
With large-membered ring ketones and imines, ring
contraction is operative leading to functionalizated fluoro
or hydroxy cyclohexanones or cycloheptanones, the driving
force being the repulsive interaction of the positive charges
in the intermediate ions.
0
1
6-(Methylacetoxy) heptan-2-one (8 ). H NMR (CDCl3) d
1.21 (d, 3J¼6.1 Hz, 3H, CH3, H-7), 1.56 (m, 4H, 2CH2, H-4
and H-5), 2.14 (s, 3H, CH3, H-1), 2.14 (s, 3H, CH3 acetate),
2.46 (t, 3J¼9.0 Hz, 2H, CH2, H-3), 4.89 (m, 1H, CH, H-6).
13C NMR (CDCl3) d 19.5 (CH2, C-4), 19.8 (2CH3, C-7),
21.2 (CH3 acetate), 29.8 (CH3, C-1), 35.3 (CH2, C-5), 43.2
(CH2, C-3), 70.4 (CH, C-6), 170.6 (CvO acetate), 208.2
(CvO, C-2). MS; m/z (%): 129 (8); 113 (100); 97 (54).
HRMS: C9H16O3 (–COCH3) calculated: 129.09155,
measured: 129.09100.
3. Experimental
3.1. General methods
The authors draw the reader’s attention to the dangerous
features of superacidic chemistry. Handling of hydrogen
fluoride and antimony pentafluoride must be done by
experienced chemists with all the necessary safety arrange-
ments in place.
0
1
5-(Methylacetoxy) heptan-2-one (9 ). H NMR (CDCl3) d
0.89 (t, 3J¼8.0 Hz, 3H, CH3, H-7), 1.57 (m, 2H, CH2, H-6),
1.81 (m, 2H, CH2, H-4), 2.05 (s, 3H, CH3, H-1), 2.15 (s, 3H,
3
CH3 acetate), 2.47 (t, J¼7.1 Hz, 2H, CH2, H-3), 4.78 (m,
1H, CH, H-5). 13C NMR (CDCl3) d 9.4 (CH3, C-7), 27.0 and
27.5 (2CH2, C-4 and C-6), 29.7 (CH3, C-1), 39.4 (CH2,
C-3), 74.7 (CH, C-5), 170.7 (CvO acetate), 207.5 (CvO,
C-2). MS; m/z (%): 129 (32); 115 (50); 113 (100). HRMS:
C9H16O3 (–COCH3) calculated: 129.09155, measured:
129.09100.
Reactions are carried out in sealed Teflonw flask with a
magnetic stirring. No further precaution have to be taken to
prevent mixture from moiety (test reaction worked out in
anhydrous conditions lead as expected to the same results).
Yields refer to isolated pure products. NMR spectra were
recorded on Bruker-300 spectrometer using chloroform-d
solvent, TMS was used as internal standard. Flash
chromatography were carried out on silica gel (Matrexw
60A/20–45 mm) and MS were recorded on INCOS 50.
3.4.2. 5-Hydroxyisoheptan-2-one and 2-hydroxy-2,5,5-
trimethyl tetrahydrofurane (10). Obtained as a mixture
(molar ratio 3/1) from ketone 3 (quenching condition A or
B) yield 82%.
5-Hydroxyisoheptan-2-one. 1H NMR (CDCl3) d 1.22 (s, 6H,
2CH3, H-6), 1.75 (t, 3J¼7.0 Hz, 2H, CH2, H-4), 2.18 (s, 3H,
CH3, H-1), 2.59 (t, 3J¼7.1 Hz, 2H, CH2, H-3), 3.32 (sl, 1H,
OH). 13C NMR (CDCl3) d 29.1 (2CH3, C-6), 29.7 (C-1),
36.7 (CH2, C-3), 38.6 (CH2, C-4), 69.7 (CH2, C-5), 209.4
(CvO).
3.2. Preparation of imines substrates
Imines were prepared by azeotropic distillation of water
with Dean–Stark apparatus, from a mixture of cyclo-
hexylamine (240 mmol), ketone (80 mmol), and anhydrous
benzene and p-tolyl sulfonic acid (catalytic). After neutral-
isation and extraction (CH2Cl2), imines were distilled.
Yields are quantitative.
2-Hydroxy-2,5,5-trimethyltetrahydrofurane. 1H NMR
(CDCl3) d 1.21 (s, 3H, CH3, H-50 or H-500), 1.38 (s, 3H,
CH3, H-50 or H-500), 1.51 (s, 3H, CH3, H-20), 2.05 (t,
3J¼6.1 Hz, 2H, CH2, H-3). 13C NMR (CDCl3) d 28.1 and
28.5 (2CH3, C-50), 30.1 (CH3, C-20), 37.5 and 38.2 (2CH2,
C-3 and C-4), 82.2 (C-5), 105.0 (C-2). MS; m/z (%): 115
(70); 113 (30); 97 (80); 72 (70); 59 (100).
3.3. Typical procedure for reaction in superacids
To a mixture of SbF5 (0.041 mol) and HF (0.300 mol) at
reaction temperature, were added substrate (2 mmol) and
CCl4 (1.2 equiv.). The reaction mixture was stirred at
reaction temperature for required time. The reaction mixture
was neutralised on water/ice (150 mL) and sodium carbon-
ate (80 g) (quenching condition A). When quenching
conditions are B, 5 mL of HF/pyridine (molar ratio 70/30)
were added on reaction mixture, stirred for 15 min, followed
by neutralisation as quenching A. The reaction mixture was
worked-up by the usual manner (extraction with CH2Cl2,
3.4.3. 6-Hydroxyisooctan-2-one (11). Obtained from
ketone 3 (quenching condition A) yield 92%. 1H NMR
(CDCl3) d 1.20 (s, 6H, 2CH3, H-7), 1.45 (t, 3J¼4.9 Hz, 2H,
CH2, H-5), 1.61 (m, 2H, CH2, H-4), 2.15 (s, 3H, CH3, H-1),
3
2.47 (t, J¼6.8 Hz, 2H, CH2, H-3), 3.28 (sl, 1H, OH). 13C
NMR (CDCl3) d 18.6 (CH3, C-1), 29.2 (2CH3, C-7), 29.8

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S. Thibaudeau et al. / Tetrahedron 58 (2002) 6643–6649
(CH2, C-4), 43.1 and 43.9 (2CH2, C-3 and C-5), 70.7 (C-6),
208.7 (CvO, C-2). MS; m/z (%): 129 (20); 126 (10); 116
(40); 111 (40); 71 (50); 58 (100). HRMS: C8H16O2–CH3
calculated: 129.09155, measured: 129.09160.
(%): 158 (10); 138 (8), 130 (20); 84 (47); 69 (100). HRMS:
C9H15FO calculated: 158.11069, measured: 158.11070.
3.5.2. 10-Hydroxy-4-isopropylcyclohexanone (28).21
Obtained from ketone 21 (quenching condition A) yield
20% 1H NMR (CDCl3) d 1.25 (s, 6H, 2CH3, H-20), 1.55 (m,
2H, 1H-3 and 1H-5), 1.81 (m, 1H, H-4), 2.20 (m, 2H, 1H-3
and 1H-5), 2.40 (m, 4H, H-2 and H-6). 13C NMR (CDCl3) d
26.9 (2CH3, C-20), 27.3 (2CH2, C-3 and C-5), 40.7 (2CH2,
C-2 and C-6), 47.1 (CH, C-4), 72.0 (C–OH, C-10), 212.6
(CvO, C-1). MS; m/z (%): 156 (10); 138 (20); 98 (68); 82
(58); 69 (100).
3.4.4. 7-Fluoroisononan-2-one (12). Obtained from ketone
1
6 (quenching condition B) yield 20%. H NMR (CDCl3) d
3
1.32 (d, JHF¼22 Hz, 6H, 2CH3, H-8), 1.56 (m, 6H, 3CH2,
H-4, H-5 and H-6), 2.14 (s, 3H, CH3, H-1), 2.46 (t,
3J¼6.9 Hz, 2H, CH2, H-3). 13C NMR (CDCl3) d 23.5 (d,
3J¼5.1 Hz, CH2, C-5), 24.0 (s, CH3, C-1), 26.6 (d,
2J¼24.2 Hz, 2CH3, C-8), 29.9 (s, CH2, C-4), 41.2 (d,
2J¼22.9 Hz, CH2, C-6), 43.6 (s, CH2, C-3), 95.5 (d,
JCF¼162.1 Hz, C-F, C-7), 209.0 (CvO, C-2). MS; m/z
(%): 141 (10); 140 (16); 122 (20); 97 (30); 82 (100). HRMS:
3.5.3. 4-[2-Fluoro-2-methyl]propylcycloheptanone (29)
and 4-[3-fluoro-3-methyl]butylcyclohexanone (31).
Obtained as a mixture (ratio molar 50/50) from ketone 24
C9H17OF–HF
calculated:
140.12011,
measured:
140.12020. C9H17OF (160.23): calculated C 67.48, H
10.69; found C 37.03, H 10.80.
(quenching condition A) yield 12%.
4-[2-Fluoro-2-methyl]propylcycloheptanone (29). 10 H NMR
3
3.4.5. 7-Hydroxyisononan-2-one (13). Obtained from
ketone 6 (quenching condition A) yield 50%. 1H NMR
(CDCl3) d 1.20 (s, 6H, 2CH3, H-8), 1.44 (m, 6H, 3CH2, H-4,
H-5 and H-6), 2.14 (s, 3H, CH3, H-1), 2,22 (sl, 1H, OH),
(CDCl3) d 1.38 (d, JHF¼21.2 Hz, 6H, 2CH3, H-3 ), 1.30–
2.6 (m, 13H). 13C NMR (CDCl3) d 22.8 (s, CH2, C-6), 27.1
and 27.3 (2d, 2J¼25.3 Hz, 2CH3, C-30), 31.3 (d, 4J¼1.9 Hz,
4
CH2, C-3), 37.2 (s, CH, C-4), 37.8 (d, J¼2.1 Hz, CH2,
3
2.46 (t, J¼6.7 Hz, 2H, CH2, H-3). 13C NMR (CDCl3) d
C-5), 42.1 and 43.6 0(s, 2CH2, C-2 and C-7), 47.6 (d,
2J¼21.5 Hz, CH2, C-1 ), 95.7 (d, JCF¼162.7 Hz, C-F, C-20),
215.0 (s, CvO, C-1).
23.7 and 24.2 (CH2, C-4 and C-5), 29.0 (2CH3, C-8), 29.6
(CH3, C-1), 43.4 and 43.5 (2CH2, C-3 and C-6), 70.5 (C–
OH, C-7), 208.9 (CvO, C-2). MS; m/z (%): 143 (8); 140
(7); 125 (40); 100 (40); 71 (64); 58 (100). HRMS:
4-[3-Fluoro-3-methyl]butylcyclohexanone (31). 1H NMR
(CDCl3) d 1.35 (d, JHF¼21.4 Hz, 6H, 2CH3, H-40), 1.30–
3
C9H18O2–H2O
140,12000.
calculated:
140.12011,
measured:
2.60 (m, 103H). 13C NMR (CDCl3) d 26.6 (d, J¼25.0 Hz,
2
2CH3, C-4 ), 29.5 (d, 3J¼5.1 Hz, CH2, C-10), 32.6 (s, 2CH2,
C-3 and C-5), 36.3 (s, CH, C-4), 39.1 (d, 2J¼22,5 Hz, CH2,
C-20), 40,7 (s, 2CH2, C-2 and C-6), 95.5 (d, JCF¼162,1 Hz,
C-F, C-30), 212.2 (s, CvO, C-1). MS; m/z (%): 186 (68);
165 (7); 149 (27); 109 (29); 95 (34); 81 (30); 55 (100).
HRMS: C11H19FO calculated: 186.14199, measured:
186.14180.
3.4.6. 5-Fluoroisoheptan-2-one (18). Obtained from imine
15 (quenching condition B) yield 68%. 1H NMR (CDCl3) d
1.33 (d, 3JHF¼21.0 Hz, 6H, 2CH3, H-6), 1.85 (m, 2H, CH2,
H-4), 2.16 (s, 3H, CH3, H-1), 2.57 (t, 3J¼8.1 Hz, 2H, CH2,
H-3). 13C NMR (CDCl3) d 26.6 (d, 2J¼23.9 Hz, 2CH3, C-6),
29.9 (s, CH3, C-1), 34.5 (d, 2J¼23.0 Hz, CH2, C-4), 38.0 (d,
3J¼3.1 Hz, CH2, C-3), 94.7 (d, JCF¼165.1 Hz, C-F, C-5),
208.1 (s, CvO, C-2). HRMS: C6H10OF, M2Me calculated:
117.07157, measured: 117.0709.
3.5.4. 4-[2-Hydroxy-2-methyl]propylcycloheptanone
(30) and 4-[3-hydroxy-3-methyl]butylcyclohexanone
(32). Obtained as a mixture (ratio molar 38/62) from ketone
24 (quenching condition A) yield 28%. Compounds 30 and
32 are separated by semi-preparative HPLC: column SI 100,
Eluent AcOEt/n-hexane: 35/65 flow: 10 mL/min, refractive
detector.
3.4.7. 6-Fluoroisooctan-2-one (19). Obtained from imine
16 (quenching condition B) yield 69%. 1H NMR (CDCl3) d
1.34 (d, 3JHF¼21.0 Hz, 6H, 2CH3, H-7), 1.64 (m, 4H, 2CH2,
3
H-4 and H-5), 2.14 (s, 3H, CH3, H-1), 2.47 (t, J¼7.1 Hz,
3
2H, CH2, H-3). 13C NMR (CDCl3) d 18.2 (d, J¼5.3 Hz,
2
CH2, C-4), 26.5 (d, J¼24.8 Hz, 2CH3, C-7), 29.9 (s, CH3,
4-[2-Hydroxy-2-methyl]propylcycloheptanone (30). 1H
NMR (CDCl3) d 1.25 (s, 6H, 2CH3, H-30), 1.40–2.10 (m,
9H, H-3, H-4, H-5, H-6 and H-10), 2.40–2,25 (m, 4H, H-2
and H-7). 13C NMR (CDCl3) d 23.0 (CH2, C-6), 29.9 and
30.1 (2CH3, C-30), 32.1 (CH2, C-3), 37.5 (CH, C-4), 38,6
(CH2, C-5), 42.3 and 43.7 (2CH2, C-2 and C-7), 50.2 (CH2,
C-10), 71.4 (C–OH, C-20), 215.0 (CvO, C-1). MS; m/z (%):
184 (2); 167 (39); 109 (75); 96 (58); 83 (56); 69 (70); 56
(100). HRMS: C11H20O2 calculated: 184.14633, measured:
184.14730.
2
C-1), 40.5 (d, J¼22.1 Hz, CH2, C-5), 43.5 (s, CH2, C-3),
95.4 (d, JCF¼150.0 Hz, C-F, C-6), 208.6 (s, CvO, C-2).
HRMS: C8H14O, M2HF calculated: 126.10447, measured:
126.1054.
3.5. Reaction of cyclic ketones and imines
3.5.1. 10-Fluoro-4-isopropylcyclohexanone (27). Obtained
1
from ketone 21 (quenching condition B) yield 60%. H
NMR (CDCl3) d 1.36 (d, JHF¼22.6 Hz, 6H, 2CH3, H-20),
3
1
1.58 (m, 2H, 1H-3 and 1H-5), 2.02 (m, 1H, H-4), 2.14 (m,
2H, 1H-3 and 1H-5), 2.36 (m, 4H, H-2 and H-6). 13C NMR
(CDCl3) d 24.4 (d, 2J¼25.1 Hz, 2CH3, C-20), 27.1 (d,
3J¼6.1 Hz, 2CH2, C-3 and C-5), 40.5 (s, 2CH2, C-2 and
C-6), 45,9 (d, 2J¼22.7 Hz, CH, C-4), 96.6 (d,
JCF¼167.1 Hz, C-F, C-10), 210.6 (s, CvO, C-1). MS; m/z
4-[3-Hydroxy-3-methyl]butylcyclohexanone (32). H NMR
(CDCl3) d 1.23 (s, 6H, 2CH3, H-40), 1.32–1.50 (m, 4H, H-3
and H-5), 1.50–1.60 (m, 2H, H-10), 1.70 (m, 1H, H-4),
2.00–2.15 (m, 2H, H-20), 2.30–2.40 (m, 4H, H-2 and H-6).
13C NMR (CDCl3) d 29.2 (2CH3, C-40), 30.0 (CH2, C-10),
32.7 (2CH2, C-3 and C-5), 36.5 (CH, C-4), 40.7 (2CH2, C-2

S. Thibaudeau et al. / Tetrahedron 58 (2002) 6643–6649
6649
and C-6), 41.4 (CH2, C-20), 70.9 (C–OH, C-30), 212.5
(CvO, C-1). MS; m/z (%):184 (2); 167 (34); 126 (28); 109
(74); 96 (58); 82 (50); 69 (68); 56 (100). HRMS: C11H20O2
calculated: 184.14633, measured: 184.14630.
3. Olah, G. A.; Mo, Y. K. J. Am. Chem. Soc. 1972, 94,
6864–6865.
4. Olah, G. A.; Renner, R.; Schilling, P.; Mo, Y. K. J. Am. Chem.
Soc. 1973, 95, 7680–7686.
5. Culmann, J. C.; Sommer, J. J. Chem. Soc., Chem. Commun.
1992, 481–483.
3.5.5. 4-[3-Fluoro-3-methyl]butylcycloheptanone (33).
Obtained from imine 26 (quenching condition B) yield
20%. 1H NMR (CDCl3) d 1.34 (d, 3JHF¼20.0 Hz, 6H, 2CH3,
H-40), 1.40–2.10 (m, 12H), 2.50 (m, 4H, 2CH2, H-2 and
H-7). 13C NMR (CDCl3) d 22.6 (s, CH2, C-6), 26.5 (2d,
2J¼24.4 Hz, 2CH3, C-40), 30.1 (s, CH2, C-3), 30.8 (d,
3J¼5.1 Hz, CH2, C-10), 36.2 (s, 1CH2, C-5), 38.9 (d,
2J¼22.9 Hz, CH2, C-20), 41.4 (s, CH, C-4), 42.1 (s, CH2,
C-2), 43.6 (s, CH2, C-7), 95.2 (d, JCF¼167.1 Hz, C-F, C-30),
214.5 (s, CvO, C-1). MS; m/z (%): 200 (20); 180 (18); 165
(20); 124 (56); 110 (90); 96 (70); 82 (85); 69 (100). HRMS:
C12H21FO calculated: 200.15764, measured: 200,15650.
6. Olah, G. A.; Parker, D. G.; Yoneda, N. Angew. Chem., Int. Ed.
Engl. 1978, 17, 909–931.
7. Olah, G. A.; Lin, H. C. J. Am. Chem. Soc. 1971, 63,
1259–1261.
8. Olah, G. A.; Gupta, B. G. B. J. Org. Chem. 1980, 45,
3532–3533.
9. Olah, G. A.; Shih, J.; Singh, B. P.; Gupta, B. G. P. J. Org.
Chem. 1983, 48, 3356–3358.
10. Olah, G. A. Angew. Chem., Int. Ed. Engl. 1973, 12, 173–212.
11. Preliminary report: Martin, A.; Jouannetaud, M. P.; Jacquesy,
J. C. Tetrahedron Lett. 1996, 37, 2967–2970.
12. Olah, G. A.; Heiliger, L.; Prakash, G. K. S. J. Am. Chem. Soc.
1989, 111, 8020–8021.
3.5.6. 4-[3-Hydroxy-3-methyl]butylcycloheptanone (34).
Obtained from ketone 25 (quenching condition A) yield
36.5% 1H NMR (CDCl3) d 1.20 (s, 6H, 2CH3, H-40), 1.25–
2.10 (m, 12H), 2.49 (m, 4H, H-2 and H-7). 13C NMR
(CDCl3) d 22.8 (CH2, C-6), 29.0 (2CH3, C-40), 30.0 (CH2,
C-3), 31.3 (CH2, C-10), 36.3 (CH2, C-5), 41.1 (CH2, C-20),
41.5 (CH, C-4), 42.0 (CH2, C-2), 43.6 (CH2, C-7), 70.6
(C–OH, C-30), 215.4 (CvO, C-1). MS; m/z (%): 198 (1);
180 (24); 165 (30); 147 (37); 125 (30); 11 (74); 97 (64); 83
(56); 69 (68); 59 (100). HRMS: C12H22O2 (FAB: MLiþ)
calculated: 205.17798, measured: 205.17720.
13. Culmann, J. C.; Simon, M.; Sommer, J. J. Chem. Soc., Chem.
Commun. 1990, 1098–1100.
14. Olah, G. A. Angew. Chem., Int. Ed. Engl. 1993, 32, 767–788.
15. Olah, G. A.; Kreinbu¨he, P. J. Am. Chem. Soc. 1967, 89,
4756–4759.
16. Olah, G. A.; Cahin, M.; O’Brien, D. H. J. Am. Chem. Soc.
1967, 89, 3568–3590.
17. Brower, D. M.; Kiffen, A. A. Recl. Trav. Chim. Pays-Bas
1973, 92, 906–914.
18. Kirchen, R. P.; Sorensen, T. S. J. Am. Chem. Soc. 1979, 101,
3240–3243.
19. Kirchen, R. P.; Sorensen, T. S.; Wagstaff, K. E. J. Am. Chem.
Soc. 1978, 100, 5134–5140.
References
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21. Cawley, J. J.; Spaziano, V. T. Tetrahedron Lett. 1973, 47,
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